Currently available immunomodulatory therapies do not modulate the pathogenesis of axonal degeneration once it is established and are only partially effective in preventing the onset of permanent disability in MS patients. Identifying a drug that stimulates endogenous myelination and spares axon degeneration would theoretically reduce the rate of disease progression. We have previously shown that treatment of demyelinating mouse models with estrogen receptor (ER)b ligand; diarylpropionitrile (DPN) has the potential for fulfilling this role. Because DPN is a generic ERb ligand with low specificity we screened higher specificity ERb and found that Indazole-Cl was the best ERb ligand. The objective is to achieve in vivo proof of principle in multiple sclerosis (MS) animal models to establish feasibility of the development candidate Indazole-Cl for MS treatment. Using the optimal dosing regimen, a direct effect of Indazole-Cl on stimulation of endogenous oligodendrocyte (OL) progenitor cell (OPC) survival and differentiation, axon remyelination, and neuroprotection is expected. Mechanisms of action will be investigated via second messenger signaling and target cell type. Translationally-relevant imaging will be used to visualize effects n a chronic MS mouse model. Moreover, assessment of Indazole-Cl-induced changes in serum cytokine and growth factors will be assessed to confirm potential biomarkers and clinical application. Eventually, safety studies to support pre-clinical candidate nomination and dossier completion will be performed. The proposed research is inspired by Indazole-Cl's strong dossier and encouraging preliminary results demonstrating its therapeutic efficacy in a chronic MS mouse model. Specifically, stimulation of endogenous remyelination and improved axon function and neurological outcomes were observed and appear mediated by increased resident OPC survival and differentiation. Quiescent OPCs exist in MS lesions and are not effectively activated by largely immunomodulatory current MS drugs. We aim to target endogenous OPCs using Indazole-Cl, thereby developing MS treatment that slows disease progression with intermittent, short-term dosing regimens.